Histone and Histone code lecture 20

Nucleosome Structure

  • DNA wraps around nucleosomes 1.7 times.
  • Interactions occur via the phosphodiester backbone, which is sequence-independent.
  • Histones play a critical role and are associated with the histone code.

Histone Structure

  • Core histones include H2A, H2B, H3, and H4.
  • Each histone has an amino-terminal tail and a carboxy-terminal tail.
  • Amino-terminal tails are important but are absent in crystal structures.

Nucleosome Assembly

  • The histone fold comprises 3 helices and 2 loops, forming the core of the nucleosome (H3-H4 dimers and H2A-H2B dimers).
  • Histone octamers are formed by the assembly of these core histones with DNA.
  • N-terminal tails are extensively interdigitated within the structure of the nucleosome.

Covalent Histone Modifications

  • Histone tails are subject to various post-translational modifications including:
    • Acetylation
    • Methylation
    • Phosphorylation
    • Ubiquitylation
    • Ribosylation
    • Sumoylation
  • Most modifications occur at residues in the flexible tails of histones (H3, H4, H2B, H2A).

Regulation of Chromatin Structure and Function

  • Changes in histone charge affect protein binding and chromatin structure.
  • Various residues (e.g., H2BK123, H3K79) are site-specific for modifications impacting chromatin functionality.

Histone Acetylation

  • Associated with active transcription, typically occurring on lysine residues.
  • Acetylation neutralizes positive charges, leading to a more hydrophilic interaction with DNA, promoting an open chromatin state.

Phosphorylation

  • Primarily occurs at serine and tyrosine residues (e.g., Serine 10 phosphorylation).
  • Changes in histone charge are a consequence of phosphorylation, influencing transcriptional activity.

Histone Methylation

  • Methylation can be mono-, di-, or tri-methylation of lysine residues (e.g., H3K4, H3K9).
  • Each methylation state has distinct implications for chromatin behavior (activation vs repression).

Functional Effects of Histone Modifications

  • H3K4 methylation: activation
  • H3K9 methylation: repression
  • H3K27 methylation: repression in euchromatin
  • H3 acetylation counters methylation effects and activates transcription.

Histone Code Hypothesis

  • Specific combinations of histone modifications define the function of chromatin.
  • Modifications alter the electrostatic charge and impact nucleic acid interactions.

Reading the Histone Code

  • Chromodomains, bromodomains, and PHD domains recognize specific modified lysine residues, influencing chromatin organization and transcriptional activity.

Histone Variants

  • Histone variants share high identity with core histones and can substitute in nucleosome formation, impacting chromatin structure and function.
  • Notable variants include H3.3, CENP-A, H2A.X, and macroH2A, each with specific roles in cellular processes such as DNA repair and regulation of transcription.